DE2060573A1 - New carboxylic acids and processes for their production - Google Patents

Description

CIBA-GIiIGY AG, BASEL (SWITZERLAND)

Case 69l6 / l + 2 / t

Germany

New carboxylic acids and processes for their production

The invention relates to new cc-phenoxyacetic acids, in which..the α-position by one or two alkyl or alkenyl radicals and the phenyl radical by one in 1-position and only monounsaturated cycloaliphatic Kohlonv / aöserstoffrest is substituted ,,. And their esters and amido,

■ 109826/1921

BATH ORIGINAL

and processes for their manufacture.

The α-position of the new compounds is primarily twice substituted and so are the substituents are preferably lower alkyl or alkenyl radicals. "Lower" denotes such alkyl or alkenyl radicals and denotes groups derived from these radicals which contain no more than 6 carbon atoms.

Lower alkyl radicals are e.g. methyl, ethyl, Propyl or isopropyl radicals or straight or branched butyl, pentyl, bonded in any position or hexyl radicals.

Lower alkenyl radicals are, for example, allyl or methallyl radicals.

The one in position 1 and only monounsaturated cycloaliphatic hydrocarbon radical can contain several rings, especially two rings, but is primarily Line is a monocyclic radical. Bicyclic radicals preferably contain rings with 5-7 ring members, the 1-4, preferably 2, carbon atoms have in common. For example, are optionally lower alkylated 1,2-dehydrodecalinyl (l) - and - (2) radicals, 2-Bicyelof2,2,2] -oeten- (2) radicals, 2-Dornenylreste and 2-Norbornenylreste called.

Monocyclic rent, i.e. 1-cycloalkenyl radicals are primarily residues with 4 - 12 and preferably

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" ^{J ! Ϊ:> !!} ™» ^{/ i: l} ! Mmem • irm ^ * m nt * -.>. ■, pp., -, ■ ■■, ■■. ■, ■■ .. ,,. ,,, ,,. ,, ,, ". ,,

5-7 ring members, such as, for example, optionally lower alkylated 1-cyclobutenyl, 1-cyclooctenyl, 1-cyclodecenyl, 1-cyclododecenyl or, in particular, optionally lower alkylating 1-cyclopentenyl, 1-cyclohexenyl or 1-cycloheptenyl radicals ".

The phenoxy radical can be unsaturated in the 1-position cycloaliphatic Kotulenwasserstoffrest in ortho position wear, but preferably wear it in meta

imd especially the para-slope. The phenyl ring can have one, two or more further, identical or different substituents. Examples of substituents include: lower alkyl groups, for example the halogen atoms mentioned, such as fluorine, bromine and, in particular, chlorine atoms, trifluoromethyl groups, nitro groups, amino groups such as di-lower alkylamino groups and acylamino groups, in which the acyl groups contain, for example, lower alkanoyl groups such as acetyl, propionyl - or butyryl groups, or \ benzoyl groups.

The esters of the new phenoxy acids are above all those with hydroxyl compounds of the formula R OH, in which R _{Q is} an aromatic radical or, above all, a radical of aliphatic character, for example a hydrocarbon radical of aliphatic character which can be further substituted, for example in the aliphatic part by amino and / or hydroxyl groups and in an optionally present aromatic ring by lower alkyl radicals, for example the

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mentioned, lower alkoxy groups, especially those mentioned lower alkyl groups containing lower alkoxy groups, halogen atoms, in particular the specified, and / or trifluoromethyl groups.

Aromatic radicals R are primarily phenyl radicals which are substituted, for example, as indicated above can.

Hydrocarbon residues of aliphatic character are those whose first, a member connected to the substituted atom is not a member of an aromatic system. Such resto are mainly aliphatic, cycloaliphatic and araliphatic radicals, v / ie e.g. alkyl and alkenyl radicals, in particular lower radicals of this type, e.g. the stated cycloalkyl radicals, e.g. the stated cycloalkenyl radicals corresponding cycloalkyl radicals, or aryl, especially phenyl-lower alkyl radicals, which the contain mentioned lower alkyl radicals.

Hydrocarbon radicals of aliphatic character substituted by hydroxyl groups are primarily hydroxyalkyl radicals, in particular 7- and especially β- hydroxy lower alkyl radicals, for example / r-hydroxyethyl, γ-hydroxypropyl or / 3,7-dihydroxypropyl. In Di- odor polyhydroxyalkyl radicals, the hydroxyl groups can also be replaced by ketones and aldehydes, especially lower alkanones and alkanals,

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such as acetone or formaldehyde, to form ketal or acetal groups be bound.

The hydrocarbon radicals of aliphatic character, optionally substituting amino "may be unsubatituiert, but are preferably mono- and disubstituted in particular. Suitable substituents are, for example, cycloaliphatic or araliphatic hydrocarbon groups may be mentioned, as those mentioned, where i aromatic rings substituted as indicated above with respect to the group R may be, but is preferably aliphatic, optionally interrupted by hetero atoms, hydrocarbon radicals, such as lower alkyl or lower, optionally by oxygen, sulfur or nitrogen atoms interrupted alkylene groups, the amino groups mentioned substituted lower alkyl groups in primarily -.. etc.

The hydroxyl compound of the formula R is OH preferably a lower alkanol such as methanol, ethanol, n- or iso-propanol or a butanol Cycloalkanol, e.g. cyclohexanol, a phenyl lower alkanol, e.g. benzyl alcohol or phenylethahol, a lower one Alkanediol or tridl, such as ethylene glycol or glycerin, or an amino lower alkanol, e.g. a di-lower alkylamino ~ lower alkanol, v / ie ß-dimethylaminoethanol, or a by a lower alkyleneamino group or by a

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Oxa-, aza- or thianiederalkylenarninogruppe substituted lower alkanol, such as a pyrrolidino-, piperidino-, morpholino- or N ¹ -Loweralkylpiperazino-lower alkanol, e.g. ß-pyrrolidinoethanol, / 3-piperidinoethanol, jß-morpholinoethanol or 3- N ¹ -methyl piperazino) ethanol.

In the amides, the amide nitrogen atom can be unsubstituted, be mono- or disubstituted, e.g. by preferably lower hydrocarbon radicals aliphatic Character, which is also interrupted by heteroatoms such as ■ oxygen, nitrogen or sulfur atoms and / or can be substituted, for example, by hydroxyl, amino, mercapto groups, or halogen atoms. In compounds with divalent hydrocarbon radicals of aliphatic character, the word "lower" is used used for residues that contain no more than 8 carbon atoms. Al-s amide substituents for example, alkyl, alkenyl or alkylene radicals are mentioned, which are also replaced by oxygen, sulfur or Nitrogen atoms interrupted and / or substituted, for example, by oxy, amino, mercapto groups, or halogen atoms could be. Particularly noteworthy as substituents are: lower alkyl and alkenyl radicals, such as e.g. the lower alkylene radicals mentioned, e.g.

Cl ^), pentylene (1.5) , hexylene (1.6) or BAD or? Gfa!

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Heptylene (2,6), cycloalkyl or cycloalkyl-alkyl radicals or corresponding radicals interrupted by the heteroatoms mentioned, such as lower alkoxyalkyl, alkylmercaptoalkyl or mono- or dialkylaminoalkyl radicals, such as 2-methoxyethyl _/ 2- adoxyethyl, 5- Mechoxypropyl, 2-methylmercaptoethyl, or dimethyl, methylethyl or diethylamino-alkyl groups, alkylenaminoalkyl groups or oxa-, aza- or thia-alkyleneamino-. alkyl groups, viobei as alkylene radicals or oxa, aza or thiaalkylene radicals, for example the radicals mentioned above or below, or oxa, aza or thiaalkylene radicals with 4-8 carbon atoms and 5-7 chain links in which the heteroatom is separated from both ends of the chain by at least 2 carbon atoms, such as 3-oxa-, 5-aza- or 2-thiapentylene-. ■ (1,5), 3-methyl-,>ethyl-> aza-hexylene ~ (l, 6), 5-aza- ' i hexylene- (l, 6) or 4-methyl-4-aza-heptylene- (2.6), or substituted radicals of this type, such as 3-chloroethyl or 5-hydroxyethyl-3-aza-pentylen- (l, 5) y or phenyl or phenylalkyl radicals that are unsubstituted or, above all, in the phenyl radical as for the Phenyl lower alkyl indicated, can be substituted. The amide nitrogen atom can, however, also be substituted by a hydroxyl or amino group.

The amino group of the amides is accordingly ins- 109826/1921

particular a free, mono- or di-lower alkylated amino groups or an optionally C-lower alkylated pyrrolidino, piperidino ^, morpholino, thiomorpholine, "piperazino, N'-lower alkylpiperazino or N '- (hydroxy-lower alkyl) -piperazino group, for example the N ¹ -methylpiperazino group or the N '- (β-hydroxyethyl) -piperazino group, or N ¹ -phenylpiperazino group, The term C-lower alkylated here, as in the following, means that the radical in question is replaced by lower alkyl radicals The new compounds have valuable pharmacological properties, especially a serum triglyceride-lowering effect, as shown in animal experiments, for example on male rats that have fasted for 24 hours, with repeated administration of 1.0-100 mg / kg po shows. However, they also have a serum cholesterol-lowering effect, as shown in the normally fed male rat egg repeated administration of 1.0-100 mg / kg po and the like nd shows in dogs after repeated administration of 10 mg / kg po. However, the new compounds also bring about a reduction in liver lipids, as shown, for example, in male rats that have fasted for 24 hours after repeated administration of 100 mg / kg po. The new compounds can therefore be used as hypolipidemic agents. But they can also serve as starting products for the production of other valuable, especially pharmacologically active ^ substances.

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Particularly noteworthy are compounds in which the phenoxy radical carries an optionally lower alkylated 1-cycloalkenyl radical in the meta- or especially para-position and can be further substituted by lower alkyl or alkoxy groups, halogen atoms and / or trifluoromethyl groups, and the α- Position is substituted by one or preferably two lower alkyl radicals, as well as their esters with lower, optionally by a lower alkylamino, lower alkylenamino or optionally C-n-alkylated pyrrolidino, piperidino, morpholine) -, thiomorpholino, piperazino-jN ' -Niederälkylpiperazino- or N ^T - (hydroxy-lower alkyl) -piperazino group substituted alkanols, or with phenyl lower alkanols, and their amides, in which the amino group is unsubstituted or a mono- or di-lower alkylamino group, a hydroxy-lower alkylamino group, a mono- or di-lower alkylamino-lower- ™

alkylamino group or an optionally C-lower alkylated pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino, N'-lower alkylpiperazino or'N '- (hydroxy-lower alkyl) -piperazino group or a phenyl-lower alkylamino group .

Compounds of the formula »

R "Ph - O - C - CO - R,

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- ίο -

wherein R is an optionally lower alkylated 1-cycloalkenyl radical with 4 - 10, preferably 5-8 ring links, Ph one optionally through lower alkyl radicals, in particular methyl, lower alkoxy radicals, in particular Methoxy, halogen atoms, especially chlorine and / or trifluoromethyl groups, substitute the p-phenylene radical and R, and Rg lower alkyl radicals, in the first place Line is ethyl or methyl and R is a lower alkoxy group, primarily methoxy or Ethoxy, an unsubstituted phenyl-lower alkoxy group, such as benzoxy or phenethoxy or, above all, the free hydroxyl group and also a free amino group, a mono- or di-lower alkylamino group or

can mean an unsubstituted phenyl lower alkylamino group ..

Are worth mentioning in the first place

Compounds of the formula I in which R is the 1-cyclopentenyl, 1-cyclohexenyl, 1-cycloheptenyl, 1-cyclononenyl radical, but in particular the 1-cycloocte.nyl radical, Ph is one substituted by methyl, methoxy or chlorine or above all unsubstituted'p-phenylene _{radical, R, and R 2 is} ethyl or preferably methyl and R is methoxy or ethoxy or in particular the free hydroxyl group, such as the ct- [p- (1-cyclopentenyl) -

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- li -

phenoxy] isobutyric acid and α- [ρ- (l-cycloheptenyl) phenoxy] isobutyric acid, but above all ct- [p- (l-cyclohexenyl)] phenoxy-isobutyric acid and especially cc- [p- (l-Cyclooctenyl) phenoxy] isobutyric acid of the formula

e.g. "on male rats with repeated administration of 1.0 mg / kg p.o. causes a significant reduction in serum lipids. ■;

The new compounds can according to known per se

Methods are made.

The preferred approach is to create an ether bridge between a phenyl radical, which is replaced by a cycloaliphatic I which is in the 1-position and only monounsaturated Hydrocarbon radical is substituted, and one in the α-position by one or two alkyl or alkenyl radicals substituted acetic acid, or an ester or amide thereof. The formation of the ether bridge can. · take place in the usual way, for example by changing

put an appropriately substituted phenol with one reactive to the alcoholic hydroxyl group esterified and in the α-position by an or

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two alkyl or alkenyl radicals substituted glycolic acid, or an ester or amide thereof.

A reactive esterified hydroxyl group is in particular one with a strong acid, such as a strong mineral acid, especially a hydrogen halide, 2.B. Hydrogen chloride or especially Hydrobromic acid, or sulfuric acid, or one damming organic acid, e.g. a sulfonic acid,

such as a lower alkanoic or benzenesulfonic acid, e.g. methanesulf on-, ethanesulfonic or p-toluenesulfonic acid, esterified Hydroxyl group. If the hydroxyl group of the glycolic acid component is esterified, the phenol can preferably be used as a salt., especially metal salt, especially alkali metal salt, e.g. sodium or potassium salt. A preferred embodiment is, for example, that a suitable α-bromo ester with the sodium salt of a corresponding phenol implemented. The implementation can take place in the usual way, in particular in an inert, preferably anhydrous, solvent and / or at elevated temperature and / or in the presence a strong base, e.g. an alkoxide, especially an alkali alkoxide such as sodium or potassium alkoxide, e.g. Sodium ethanolate or methoxide.

The formation of the ether bridge can also take place in such a way that a mixed ester of carbonic acid with a corresponding phenol on the one hand and one as indicated

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substituted glycolic acid or an ester or amide thereof on the other hand decomposed with the elimination of carbon dioxide. The decomposition can take place in the usual way, in particular by heating.

Another method for the preparation of the new compounds is that one in an anisole, which am Benzene ring by one in 1-position and only simply unsaturated cycloaliphatic hydrocarbon radical is substituted and on the methyl group by a or two alkyl or alkenyl radicals and by one in a free, esterified or amidated to carboxyl group convertible radical X is substituted, X converted into a free, esterified or amidated carboxyl group. Such a radical X is in particular one which is free, esterified or converted by hydrolysis, alcoholysis or aminolysis amidated carboxyl group transferable residue, e.g. a reactive modified carboxyl group with the exception of a { esterified or amidated carboxyl group, such as an acid halide, e.g. acid chloride or acid anhydride grouping or a cyano group or a trihalomethyl group, where the halogen, Ctilor, bromine or iodine can be.

The hydrolysis to the, free carboxyl group or _; if one starts from a cyano group, also to the amidated carboxyl group, takes place in a known manner, for example in the presence of a strong base such as an alkali metal hydroxide, for example.

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Sodium or potassium hydroxide or in the presence of a strong acid such as a mineral acid such as hydrochloric acid.

The alcoholysis to an esterified carboxyl group takes place in the usual way, e.g. by reacting with a corresponding alcohol, expediently in the presence of acidic or basic agents. Assuming a cyano compound, one works e.g. in the presence of a mineral acid, like sulfuric acid, and advantageously in the presence of ammonium chloride, if you borrow from an acid halide or anhydride, you mainly use basic condensing agents, such as strong bases, e.g. those mentioned, or alkali carbonates, such as sodium or potassium carbonate, or organic bases, e.g. pyridine or triethylamine.

Aminolysis is mainly based on acid halides or anhydrides, and sets with ammonia or on the nitrogen atom amines containing at least one hydrogen atom, such as hydrazine or hydroxylamine to. The reaction is carried out in the usual way, if desired, in the presence of acid-binding agents, such as organic or inorganic bases, e.g. those mentioned.

The new compounds are also obtained if, in a compound corresponding to the compounds according to the invention, which ^{carries a removable radical Y 1} in the α-position to the free or modified carboxyl group, the

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Remainder Y ^{1 is} split off.

Y ¹ is in particular an acyl radical, such as an acyl radical derived from an aliphatic or araliphatic carboxylic acid, for example a lower alkanecarboxylic acid or phenyl-lower alkanecarboxylic acid, such as the acetyl radical, but above all a carboxyl radical. The cleavage can take place in the customary manner, in the case of a carboxyl radical Y ', for example by heating, if appropriate in the presence of an inert solvent, for example diphenyl ether or pyridine. I.

In the compounds obtained, substituents can be introduced, modified or split off within the scope of the end products.

For example, free, esterified and amlated carboxyl groups can be incorporated into one another in the compounds obtained convert.

Esterified carboxyl groups and amidated carboxyl groups, dii. Carbamyl groups can be added in the usual way, e.g. by hydrolysis, preferably in the presence of strong *

Bases or strong acids, e.g. those mentioned above, can be converted into free carboxyl groups. If desired, you can in the hydrolysis of carbamyl groups oxidizing agents, like nitric acid, add.

Free or esterified carboxyl groups can also be converted into carbarnyl groups in the usual way, e.g. by reaction with ammonia or amines having at least one hydrogen atom on the nitrogen atom and optionally

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- ιβ -

Dehydration of the intermediate ammonium salt. Free carboxyl groups can be esterified in the usual way, for example by reacting with a corresponding alcohol, advantageously in the presence of an acid such as a mineral acid, e.g. sulfuric acid or hydrochloric acid, or in the presence of a water-binding agent such as dicyclohexylcarbodiimide, or by reacting with a corresponding diazo compound, e.g. a diazoalkane. The esterification can also be carried out by reacting a salt, preferably an alkali metal salt, of the acid with a reactive esterified alcohol, for example a halide, such as chloride, of the corresponding alcohol.

Free carboxyl groups can, for example, also be converted into acid halide or anhydride groups in the usual way, for example by reaction with halides of phosphorus or sulfur, such as thionyl chloride, phosphorus pentachloride or phosphorus tribromide, or with acid halides such as chloroformic acid esters or oxalyl chloride. The acid anhydride or halide groups can then be converted into esterified carboxyl groups or carbamyl groups in the usual way by reaction with appropriate alcohols, if desired, in the presence of acid-binding agents, such as organic or inorganic bases, or with ammonia or suitable amines.

In compounds obtained, the nitro groups on

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Contain a phenyl ring, these can be reduced to amino groups, e.g. with iron and hydrochloric acid.

In compounds obtained that have a. contain free amino group, this can be acylated. the Acylation takes place in the usual way, in particular with reactive, functional derivatives of the relevant Acids, preferably acid halides or anhydrides, if necessary in the presence of acid-binding agents, e.g. basic

Means, such as those mentioned, or, if necessary, in "

Essence of acids, e.g. those mentioned above. Conversely, one can also use the acylamino groups in compounds obtained wear on the benzene ring, split off the acyl residues. The cleavage takes place in the usual way, e.g. as above for the hydrolysis given for the free carboxyl group.

In esters obtained in which the alcoholic component contains hydroxyl groups, which are replaced by ketones or Aldehydes are bound to ketal or acetal groups, '| the ketal or acetal groups can be hydrolyzed. The hydrolysis can be carried out in the usual way, especially in the presence of acids, e.g. one of the above or acetic acid.

The reactions mentioned are carried out in the usual way in the presence or absence of dilution, condensation, and / or catalytic agents, in the case of lowered, habitual. 1 safe or elevated temperature, if necessary at low

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closed vessel and / or carried out in an inert gas atmosphere,

Depending on the process conditions and starting materials, salt-forming end products may be obtained in free form or in the form of their salts, which can be converted into one another or into andoe salts in the usual way. So acidic end products are obtained, i.e. those in which a free carboxyl group is present, in free form or in form their size with bases. The free acidic compounds obtained can be used in the usual way, e.g. by reacting with appropriate basic agents, in the safe, with bases, especially in therapeutically usable salts with bases, e.g. salts with organic amines, or metal salts are converted. The metal salts are mainly alkali metal salts or alkaline earth metal salts, such as sodium, potassium, magnesium or Calcium salts into consideration. Free acids can be extracted from the salts in the usual way, e.g. by reaction with acidic Funds, release. End products with a basic character can also be obtained in free form or in the form of their salts. The salts of the basic end materials can be used in a manner known per se, e.g. with alkalis or ion exchangers be converted into the free bases. The latter can be converted by reaction with organic or inorganic ■ Acids, especially those that are used to form therapeutically

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Usable salts are suitable to win salts. As such Examples of acids are: hydrohalic acids, Sulfuric acids, phosphoric acids, nitric acid, perchloric acid j aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, Amber, glycol, milk, apple, wine, lemon, asebrbin, Maleic, hydroxymaleic or pyruvic acid; Phenyl acetic acid, Benzoin, p-aminobenzoe, anthranil, p-hydroxy {

benzoic, salicylic or p-aminosalicylic acid, emboxylic acid, Methanesulphonic, ethanesulphonic, hydroxyethanesulphonic, ethylene sulphonic acid; Halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic acids or sulfanilic acid; Methionine or tryptophan, lysine or arginine.

These and other salts can also be used to purify the new compounds, for example by converting the free compounds into their salts, isolating them _Λ and converting them back into the free compounds. As a result of the close relationships between the new compounds in free form and in the form of their salts, the corresponding salts are to be understood in advance and subsequently under the free compounds, meaningfully and appropriately.

The new compounds can, depending on the choice of starting materials and working methods and depending on the number of asymmetric carbon atoms, as optical antipodes,

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Racemates or as mixtures of isomers (e.g. mixtures of racemates).

Isomer mixtures obtained (mixtures of racemates) can be due to the physico-chemical differences of the Components separated into the two stereoisomeric (diastereomeric) pure isomers (e.g. racemates) in a known manner for example by chromatography and / or fractional crystallization.

Racemates obtained can be broken down into the optical antipodes by known methods, for example by recrystallization from an optically active solvent, with the help of microorganisms, or by converting a free one Carboxylic acid with an optically active base which forms salts with the racemic compound and separation of the on this Salts obtained in this way, e.g. due to their different solubilities, into the diastereomers; from these you can then the antipodes are released by the action of suitable means. A particularly common optically active base is e.g. the D and L forms of cinchonine. It is advantageous to isolate the more effective of the two antipodes.

Obtained racemates of basic compounds can also be broken down into the optical antipodes by reacting the racemic compound with an optically active acid which forms salts with it and the obtained in this way Salts, e.g. due to their different solubilities,

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separates into the diastereomers. From the diastereomers " then the antipodes are released by the action of suitable means. Optically active acids commonly used are e.g. the D- and L-porraen of tartaric acid, di-o-toluyl- tartaric acid, malic acid, mandelic acid, camphorsulfonic acid or Quinic acid.

The invention also relates to those execution

forms of the process, according to which one can move from one

one stage of the process obtainable as an intermediate product

Connection goes out and the missing process steps are carried out, or in which a starting material under the reac-. tion conditions forms, or in which a reaction component is optionally present in the form of its isomers, racemates or optical antipodes and / or in the form of their salts. So you can, for example, a phenol that by

a 1-position, and only mono-unsaturated cycloaliphatic hydrocarbon radical is substituted with an a in α-position by one or two alkyl or Alkenylresfce substiMerten glycolic acid or an ester or amide thereof in the presence of an ester of carbonic acid 'as a Diarylearbonats, for example diphenyl carbonate, or in particular a di-lower alkyl carbonate, for example dimethyl carbonate or diethyl carbonate. In the process, the abovementioned mixed carbonic acid ester is formed as an intermediate, which then, according to the invention, splits off carbon dioxide; The reaction is preferred

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at elevated temperature, e.g. between about 100 ° C and about 210 C, preferably between about 180 ° C and about 200 ° C, if desired, in the presence of a transesterification catalyst, such as an alkali metal carbonate, e.g. sodium lower alkanolate, and preferably carried out in the absence of a further diluent.

But you can also start from a half ester or ester of carbonic acid in which one of the desired in the end product Substituents of the ether bridge, preferably the phenolic radical, is included and the second hydroxyl group the carbonic acid etherified, especially etherified with a volatile alcohol or else through a halogen atom is replaced, and react with a hydroxyl compound containing the other substituents of the ether bridge. A fleeting one Alcohol is primarily a lower alkanol, e.g. methanol or ethanol. A halogen atom is primarily a Chlorine or bromine atom. This reaction is expediently carried out under the same conditions as those above and the same intermediate product is also formed.

You can also use a phenol, which is in the 1-position and only monounsaturated cycloaliphatic Hydrocarbon radical is substituted, in the presence of a tri- or tetrahalogenated methane derivative and a strong one

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Base with one derived from an alkane or alkene React aldehyde or ketone. An anisole which is substituted as described above is formed as an intermediate, in which X is a trihalomethyl group and then according to the invention is hydrolyzed to the corresponding acid. A trihalogenated methane derivative is primarily used here Chloroform, but can also 1,1,1-triehloraeeton, bromoform, 1,1,1-tribromoacetone, iodoform, chloral, chloral hydrate, bromal or Be bromine hydrate; Tetrahedral methane derivatives are e.g. carbon tetrachloride and carbon tetrabromide. One strong base is in particular an alkali metal hydroxide e.g. Sodium or potassium hydroxide. The reaction is preferably carried out at an elevated temperature and in the presence of a diluent, that also from an excess of the aldehyde or of ketone can commit.

Appropriately one uses for the implementation of the

reactions according to the invention those starting materials that lead to " the groups of end products especially mentioned at the beginning and especially those specifically described or highlighted Lead end materials.

The starting materials are known or, if they are new, can be prepared by methods known per se.

Those used as preferred starting materials

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by a cycloaliphatic which is unsaturated in the 1-position Hydrocarbon radical substituted phenols can be prepared by a suitable cyclic ketone with a Reacts lower alkoxyphenyl Grignard compound, splits off water and the lower alkoxy group, preferably by treatment hydrolyzed with pyridine hydrochloride.

The new compounds can be used, for example, in the form of pharmaceutical preparations, which they can be used in free In the form or, if appropriate, in the form of their salts, especially the therapeutically useful alkali metal salts, as a mixture with a pharmaceutical, organic or inorganic, e.g. suitable for enteral or parenteral administration, contain solid or liquid carrier material. For the formation of the same substances come into question that do not react with the new compounds, such as water, gelatin, lactose, starch, stearyl alcohol, magnesium stearate, Talc, vegetable oils, benzyl alcohol, rubber> ropylene glycols, Petroleum jelly or other known excipients. The pharmaceutical preparations can e.g. as tablets, drage * es, Capsules, suppositories or in liquid "form as solutions (e.g. as elixir or syrup), suspensions or emulsions are present. If necessary, they are sterilized and / or contain auxiliary substances such as preservatives, Stabilizers, wetting agents or emulsifiers,

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Solubilizers or salts to change the osmotic vision Pressure or buffer. You-can also help others therapeutically contain valuable substances. The pharmaceutical preparations are obtained using customary methods.

The invention is described in more detail in the following examples. The temperatures are given in degrees Celsius.

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example 1

33.2 g of p- (1-cycloheptenyl) phenol are added with stirring to a solution of 4.5 g of sodium in 200 ml of absolute ethanol added. As soon as the substance has dissolved, 37 * 2 g of ethyl α-bromoisobutyrate are added dropwise and then warms up to 50 for 20 hours. It is evaporated in a vacuum, the residue is taken in 500 ml Methylene chloride and filtered off from the precipitated sodium bromide. The methylene chloride solution is 2 times with 100 ml ice cold 2-n. Sodium hydroxide solution extracted, then washed neutral with water, dried over sodium sulfate and im Evaporated in vacuo. The residue is distilled in a Claisen flask under high vacuum and ethyl a- [p- (l-cyeloheptenyl) phenoxy] isobutyrate is obtained the formula

as a viscous oil with a b.p. 143-145 ° (0.02 mm Hg).

The p- (l ~ cycloheptenyl) -phendHc used as starting material in this example can be used as follows getting produced:

To a vigorously stirred suspension of 28.4 g

Mg turnings washed with chloroform and activated with iodine

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a solution of 1 & 7 g of p-broraanisole in 500 ml of absolute ether is added in portions to 1000 ml of absolute ether in such a way that the Grignard reaction can be maintained gently. The reaction is allowed to continue for a further hour, the mixture is cooled to 15 ° and 128 g of cycloheptanone are added dropwise. After the reaction mixture has been stirred for a further 5 hours, ice and saturated ammonium chloride solution are added. It is extracted with ether, the ethereal layers are washed with water, dried over sodium sulfate and evaporated in vacuo. The oily residue already suffers from splitting off of water during the distillation in a water jet vacuum. In this way, p- (1-cycloheptenyl) - 'anisole with a boiling point of 178-182 ° is obtained

70 g of p- (l-cycloheptenyl) anisole and 155 S

Pyridine hydrochloride are mixed well and heated to 180 ° in a nitrogen atmosphere for K hours. It is cooled, mixed with water and extracted with benzene. The benzene λ extracts are> times with 100 ml 1-n. Sodium hydroxide solution shaken out. The alkaline phase is 2-n. Acidified hydrochloric acid and extracted with ether; the ethereal solution is dried over sodium sulfate and evaporated. The residue recrystallized from benzene gives the p- (l-cycloheptenyl) phenol from P. 88-92 °.

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Example 2

A solution of 24.2 g of a- [p- (l-Cycloheptenyl) - ' phenoxy] isobutyric acid ethyl ester in 150 ml of ethanol is with l80 ml 2-n. Sodium hydroxide solution and added for 2 hours

60 heated. It is then evaporated in a vacuum, mixed with water, extracted with ether and acidified the aqueous layer with 2-n. Hydrochloric acid. The excreted oil becomes ether added, the ether layer dried over sodium sulfate and evaporated in vacuo. After recrystallizing the Solid residue from petroleum ether gives a- [p- (l-cycloheptenyl) phenoxy] isobutyric acid the formula

cooH

as white crystals with a temperature of 101 - 105 °.

That produced from the carboxylic acid in the usual way Sodium salt melts at 278-282 °.

109826/1921

Example 5

To a solution of 1.46 g of sodium in 70 ml

10 g of p- (l-cyclohexenyl) phenol are added to absolute ethanol while stirring added. As soon as this substance has dissolved, 12) g of ethyl ct-bromoisobutyrate are added dropwise and then heated at 50 for 16 hours. Man then evaporates in vacuo, takes the residue in 500 ml Aether on, filtered off from the precipitated sodium bromide and washes the ether phase twice with 20 ml each ice cold 2-n. Caustic soda and with water. After drying over sodium sulfate, it is evaporated in vacuo and the a- [p_ (l-Cyclohexenyl) phenoxy] isobutyric acid ethyl ester formula

as a pale yellow oil,

. , Which in this example is used as the starting material

p * (l ~ cyclohexenyl) -phenol used can be as follows

■, ^l
manufactured stoves:

.To a. Suspension of 72 g of magnesium turnings (washed with chloroform and activated with iodine) in 1000 ml

109826/1921

absolute tetrahydrofuran is added dropwise with stirring "a solution of yjh g of p-bromanisole in 600 ml of absolute tetrahydrofuran in such a way that the Grignard reaction that has started can be gently maintained. At the end, stirring is continued for 1 1/2 hours at 60 °, then cools to 20 ° and 294 g of cyclohexanone are added dropwise, taking care that the temperature does not rise above 50 °. The reaction is then allowed to continue for 1 hour at the same temperature, then evaporated in vacuo, ice and approx. 1600 ml of saturated ammonium chloride solution and extracted with ether. The solution, dried over sodium sulfate and evaporated in vacuo, gives an oily residue. After distillation from a Vigreux flask, p- (1-hydroxy-1-cyclohexyl> -anisole of bp 165 is obtained (11 mm Hg.).

299 g of this compound are in 1100 ml

Glacial acetic acid dissolved, with 500 ml of 2-n. Salsic acid is added and the mixture is heated to 100 ° for one hour. It is cooled to 20 °, water is added and the mixture is extracted with ether. The essential extracts are numbered three times with 2-n. ., And evaporated sodium bicarbonate solution dried over sodium sulfate in vacuo, after fractional distillation from "a Claisenkolben obtains the p- (l-cyclohexenyl) -anisole from Kp I58 -. I60 mm Hg). -

56.5 g of p- (1-cyclohexenyl) anisole and 125 β 109826/1921

Pyridine hydrochloride are mixed well and heated to 180 ° for J hours in a nitrogen atmosphere. It is cooled to room temperature, mixed with water and extracted three times with 400 ml of benzene each time. The benzene extracts, washed three times with> 00 ml of water each time, are dried over sodium sulfate and evaporated in vacuo. The solid residue provides the crude p- (l-cyclohexenyl) phenol from P. 115-119 » which can be purified by recrystallization from benzene and then

melts at 120 - 122.

109826/1921

Example 4

A solution of 12.5 g «- [p- (l-Cyclohexenyl) phenoxy] isobutyric acid ethyl ester in 150 ml of ethanol is mixed with 100 ml of 2-n. Sodium hydroxide solution is added and the mixture is heated to 60 for 2 hours. It is then evaporated on a rotary evaporator in vacuo, the aqueous solution is mixed with concentrated hydrochloric acid until an acidic reaction is obtained and extracted with ether. The ether layer is washed neutral with water, dried over sodium sulfate and evaporated in vacuo. The residue is recrystallized from ether-petroleum ether and the α- [p- (l-cyclohexenyl) phenoxy] isobutyric acid of the formula is obtained

COOH

as white crystals from F. 115 - H5 · »

The sodium salt prepared in the usual way from the carboxylic acid melts at 281-284 °.

10 9 8 2 6/1921

Example 5

To a solution of 1.7 g of sodium in 80 ml of absolute ethanol, 10.7 g of p- (l-cyelopentenyl) phenol are added with stirring. Once everything has gone into solution, is added dropwise 14, ¹ I- a-g ~ Bromisobuttersäureätb.yl ester and erNärmt the reaction mixture for 16 hours at 50th After evaporation in vacuo, the residue is _similar in 200 ml methylene chloride, is filtered off from the precipitated sodium bromide and washing the methylene chloride phase twice with 50 ml of ice-cold 2-n. Caustic soda and with water. ' The organic extract, dried over sodium sulfate and evaporated in vacuo, gives the crude ethyl a- [p- (l-cyclopentenyl) phenoxy] isobutyrate of the formula

GH ₃
0 - C - C00 _o H_

as a weak brown oil,

The p- (1-cycl.opentenyl) phenol used as the starting material in this example becomes as follows manufactured:

To a well-stirred suspension of 28.4 g washed with chloroform and activated with iodine

109826/1921

shavings in 1000 ml of ether are added in portions a solution of 187 g of p-bromanisole in 500 ml of ether so that the Grignard reaction proceeds with a gentle reflux. At the end, the mixture is boiled for a further hour, then cooled to 15 and 84 g of cyclopentanone are added dropwise while stirring. After getting a. Has stirred at room temperature for an hour, ice and a saturated ammonium chloride solution are added. The ether phase is washed with water, dried over sodium sulfate and evaporated in vacuo. When distilling from a ^c laisen flask in a water jet vacuum, water is split off directly. The solid p- (l-cyclopentenyl) anisole distills at 155-165 (18 mm Hg) and, after recrystallization from ethanol, melts at 88-89

10 g of p- (l-cyclopentenyl ^ anisole and 27.5 g of pyridine hydrochloride are mixed thoroughly and heated to 150 for 3 hours in a nitrogen atmosphere. It is cooled, mixed with 200 ml of water and extracted three times with 100 ml of benzene each time Benzene extracts are washed with water and then extracted three times with 150 ml of 1N sodium hydroxide solution each time. The alkaline extracts are first acidified with 2N hydrochloric acid and then extracted with ether. The ether extracts, dried over sodium sulfate and evaporated in vacuo, give a solid residue This is dissolved in toluene, filtered through silica gel and recrystallized after evaporation from benzene-petroleum ether to give the p- (l-cyclopentenyl) -phenol from P. 14) -. is obtained 146th

109826/1921

Example 6

A solution of 12.2 g of cc ~ [p- (l-cyclopentenyl) -phenoxyj-isobutyric acid ethyl ester in 100 ml of ethanol is mixed with 100 ml of 2-n. Sodium hydroxide solution is added and the mixture is heated to 60 ° for 2 hours. It is then evaporated in vacuo, added. with water and extracted with ether. The aqueous phase is acidified with concentrated hydrochloric acid and extracted with ether. The ethereal extracts, dried over sodium sulphate and evaporated in vacuo, give a solid residue, from which the α- [p- (l-cyclopentenyl ^N -phenoxy] -isobutyric acid of the formula) is obtained by recrystallization from ether-petroleum ether.

is obtained as white crystals from P. 100 - 102 °.

The sodium salt, which is produced in the usual way from the carboxylic acid, melts at 266-268.

109826/1921

Example 7

10 g of p- (1-cyclohexenyl) phenol are added to a solution of 1.46 g of sodium in 70 ml of absolute ethanol while stirring. As soon as this substance has dissolved, 10 g of ethyl α-bromopropionate are added dropwise and the mixture is then heated at 50 for 16 hours. After evaporation in vacuo, the residue is taken up in 300 ml of ether, the precipitated sodium bromide is filtered off and the ether phase is washed twice with 20 ml of ice-cold 2N each time. Caustic soda and with water. After drying over sodium sulfate, it is evaporated in vacuo and the ethyl a- [p- (l-cyclohexenyl) phenoxy] propionate of the formula is obtained

OH,

0 - CH - COOG ₀ HL £ 5

as a pale yellow oil.

109826/1 921

Example 8

A solution of 12.2 g of ethyl a- [p- (l-cyclohexenyl) phenoxy] propionate in 150 ml of ethanol is mixed with 100 ml of 2-n. Sodium hydroxide solution and added for 2 hours 60 heated. It is then evaporated on a rotary evaporator in vacuo, and concentrated water is added to the aqueous solution Hydrochloric acid until acidic and extracted with ether. The ether layer becomes neutral with water washed, dried over sodium sulfate and evaporated in vacuo. The solid residue is made from ether-petroleum ether recrystallized and the α- [p- (l-cyclohexenyl) phenoxy] propionic acid is obtained formula

OH,

\> - 0 - GH - COOH

as white crystals from P. 127 - 1> 0 °.

The sodium salt produced in the usual way from the carboxylic acid melts above 300 ° and is in water soluble to more than $ 10.

109826/1921

Example 9

To a solution of 2.15 g of sodium in 80 ml of absolute Ethanol is added while stirring 22 g of p- (l-cyclododecenyl) phenol added. As soon as the substance has dissolved, 18.5 g of ethyl α-bromoisobutyrate are added dropwise and then heated to 50 ° for 16 hours. It is then evaporated in vacuo, the residue is taken in 500 ml ml of methylene chloride, the precipitated sodium bromide is filtered off and the methylene chloride solution is washed twice with 50 ml each ice-cold 2-n. Caustic soda and with water. To after drying over sodium sulfate, it is evaporated in vacuo and the ethyl α- [p- (l-cyclododecenyl) phenoxy] isobutyrate is obtained the formula

C-COOC ₀ H ₁ , I 2 5

CH.

as a pale yellow oil.

The p- (1-cyclododecenyl) phenol used as a starting material in this example can be prepared as follows will:

To a suspension of 15.7 g with chloroform

109826/1921

wash and magnesium shavings activated with iodine. in 5OO ml absolute tetrahydrofuran is added dropwise with stirring to a solution of 95 × 5 g of p-bromanisole in 100 ml of absolute tetrahydrofuran in such a way that the reaction that has started can be mildly maintained. At the end you stir another 1 hour at 60 °, then cools to 15 and added dropwise with a solution of 91 * 6 g of cyclododecanon in 100 ml of absolute tetrahydrofuran. The reaction is then allowed to continue for 6 hours at room temperature, then evaporated in vacuo, mixed with ice and ammonium chloride solution and extracted with ether. The over sodium sulfate The dried and evaporated solution leaves a solid residue which precipitates out after recrystallization Petroleum ether provides p- (l-hydroxycyclododecyl) anisole with a temperature of 115-117 °.

68 g of this compound are dissolved in 400 ml of glacial acetic acid

dissolved, with 200 ml 2-n. Hydrochloric acid and heated for a similar hour at 100 °. It is cooled to 20 °, water is added and the mixture is extracted with ether. The essential extracts are numbered three times with 2-n. Washed sodium hydrogen carbonate solution, dried over sodium sulfate and evaporated in vacuo. After the fractional distillation in a high vacuum, the p- (l-cyclododecenyl) anisole is obtained with a boiling point of 165-170 ° (0.02 mm Hg).

58 g of p- (1-cyclododecenyl) anisole and 125 g of pyri-

109826/1921

2060571

Din hydrochloride are mixed well and kept for 5 hours heated to 180 in a nitrogen atmosphere. It is cooled to room temperature, water is added and the mixture is extracted three times with benzene. The benzene solution washed with water is with 2-n. Sodium hydroxide solution shaken, with a white solid Precipitation occurs. This is filtered off, suspended in water and treated with 2-n. Acidified hydrochloric acid. One extracts with ether, dry the ethereal phases over sodium sulphate and evaporate them in a vacuum. The residue consists of crude p- (l-cyclo.dodecenyl) phenol from F. 117-120.

109826/1921

208057:

Example 10

A solution of 19 g of α- [ρ- (l-Cyclododecenyl) -phenoxy] -isobuttersaurethylester in 200 ml of ethanol is with 120 ml of 2-n, sodium hydroxide solution added and during. Heated to 60 for 2 hours. It is then evaporated on a rotary evaporator in vacuo a, the aqueous solution is treated with concentrated hydrochloric acid until an acidic reaction and extracted with ether. the The ether layer is washed neutral with water, dried over sodium sulfate and evaporated in vacuo. The oily one The residue is the crude α- [ρ- (l-cyclododecenyl) phenoxy] isobutyric acid the formula

CH.

represents, which can be distilled in a high vacuum and the 200-205 ° (0.05 mm Hg).

That produced from the carboxylic acid in the usual way Sodium salt melts at 220-2 ^ 0.

109826/1921

Example 11

To a solution of 5 * 8 g of sodium in 300 ml of absolute Ethanol is added to 46 g of p- (l-cyclooctenyl) phenol with stirring. As soon as the substance has gone into solution, added one drops dropwise with 49 * 3 S a-bromoisobutyric acid ethyl ester and then heated to 50 ° for 20 hours. It is evaporated in vacuo and the residue is taken up in 500 ml of methylene chloride on and filtered off from the precipitated sodium bromide. The methylene chloride solution is 2 times with 100 ml of 2-n. ice cold Shaken out sodium hydroxide solution, then washed neutral with water, dried over sodium sulfate and evaporated in vacuo. The residue is distilled in a Claisen flask under high vacuum and cen α- [p- (1-cyclooetenyl) phenoxy] ethyl isobutyrate is obtained the formula

as a viscous oil of bp 152-155 (0.02 mm Hg).

The p- (1-cyclooctenyl) phenol used as a starting material in this example can be prepared as follows will:

To a vigorously stirred suspension of 19 * 5 g with

Magnesium turnings washed with chloroform and activated with iodine

109826/1921

In 8OO ml of absolute tetrahydrofuran, a solution of 13I g of p-bromanisole in 200 ml of absolute tetrahydrofuran is added in portions so that "the Grignard reaction can be maintained gently. The reaction is allowed to continue for an hour, cool to 15 and added dropwise 88 g of cyclooctanone After stirring the reaction mixture for a further 5 hours, ice and saturated ammonium chloride solution are added, the mixture is extracted with ether, the ethereal layers are washed with water, dried over sodium sulphate and evaporated in vacuo Oily residue already undergoes elimination of water during the distillation in a high vacuum. In this way, p- (1-cyclooctenyl) anisole with a boiling point of 115-118 ° (0.05 mm Hg) is obtained.

80 g of p- (1-cyclooctenyl) anisole and 175 g of pyridine hydrochloride are mixed well and heated to 180 for 4 hours in a nitrogen atmosphere. It is cooled, mixed with water and extracted with benzene. The benzene- % extracts are 5 times with 100 ml 1-n. Sodium hydroxide solution shaken out. The alkaline phase is 2-n. Acidified hydrochloric acid and extracted with ether; the ethereal solution is dried over sodium sulfate and evaporated. The residue recrystallized from benzene-Pe trolether yields the p- (l-cyclooctenyl) phenol from P. 95-97 °.

109826/1921

Example 12

■ A solution of 4-9 g of a- [p- (l-Cyclooctenyl) phenoxy] ■ ethyl isobutyrate in 500 ml of ethanol is mixed with 250 ml 2-n. Sodium hydroxide solution is added and the mixture is heated to βθ for 2 hours. It is then evaporated in vacuo, water is added, the mixture is extracted with ether and the aqueous layer is acidified "2-n. Hydrochloric acid. The precipitated oil is taken up in ether, the ether layer dried over sodium sulfate and evaporated in vacuo. After recrystallizing the Solid residue from ether petroleum ether gives oc- [p- (1-cyclooctenyl) phenoxy] isobutyric acid the formula

as white crystals from P. 80-82.

The usual way from the carboxylic acid on Herge introduced sodium salt melts at 273-276 ^0th

109826/1921

Example I5

A solution of 2.7 g of sodium in 150 ml of absolute Ethanol is mixed with 20 g of p- (4-methyl-1-cyclohexenyl) phenol while stirring offset. As soon as this substance has dissolved, 25 g of ethyl oc-bromoisobutyrate are added dropwise added and heated for 16 hours at 50 °. It is then evaporated in vacuo, the residue is taken in 500 ml of ether and filtered off from the precipitated sodium bromide. The ethereal solution becomes ice-cold twice with 20 ml each time 2-n. Sodium hydroxide solution and washed with water. After drying over sodium sulfate, it is evaporated in vacuo and obtained the ethyl α- [p- (4-methyl-1-cyclohexenyl) phenoxy] isobutyrate the formula

0-C — COOC ₀ H ₁ -

CH i

as a pale yellow oil.

The p- (4-methyl-1-cyclohexenyl) phenol used as the starting material in this example can be as follows getting produced:

To a suspension of 28.4 g of magnesium shavings (Washed with chloroform and activated with iodine) in 500 ml of absolute ether is added dropwise with stirring

109826/1921

Add a solution of 187 g of p-bromanisole in 500 ml of absolute ether in such a way that the Grignard reaction that has started can be gently maintained. At the end the mixture is stirred for a further hour at βθ, then cooled to 20 ° and 112 g of ² l-methylcyclohexanone are added dropwise, taking care that the temperature does not rise above 30 °. The mixture is then left to react for a further 1 hour at the same temperature, then evaporated in vacuo, ice and saturated ammonium chloride solution are added and the mixture is extracted with ether. The solution, dried over sodium sulfate and evaporated in vacuo, gives an oily residue. This suffers from dehydration during the distillation in a high vacuum. In this way, p- (4-methyl-1-cycylohexenyl) anisole with a boiling point of Il4-116 (0.04 mm Hg) is obtained.

^ 9 ^ 2 g of p- (4-methyl-l-cyclohexenyl) anisole and II5 g Pyridine hydrochloride are mixed well and heated to 180 for 4 hours in a nitrogen atmosphere. Man cools, mixed with water and extracted with benzene. The benzene extracts are 5 times with 100 ml 1-n. Caustic soda shaken out. The alkaline phase is 2-n. Acidified hydrochloric acid and extracted with ether; the essential solution is dried over sodium sulfate and evaporated. The residue recrystallized from benzene yields p- (4-methyl-1-cyclohexenyl) phenol from P. IO6-IO7

109826/1921

2060S73

Example 14

A solution of 20.5 S <* - Ep- (4-methyl-1-cyclohexenyl) -phenoxy] -isobutyric acid ethyl ester in 200 ml of ethanol is mixed with 120 ml of 2-n. Sodium hydroxide solution added and for 2 hours heated to 60. ' It is then evaporated in vacuo, added with water, extracted with ether and acidify the aqueous layer with 2-n. Hydrochloric acid. The solid matter excreted is taken up in ether, the ether layer is dried over sodium sulfate and evaporated in vacuo. After this When the solid residue is not crystallized from ether-petroleum ether, et- [p- (4-methyl-1-cyclohexenyl) phenoxy] isobutyric acid is obtained the formula

as white crystals with a temperature of 105-105 °.

The sodium salt prepared in the usual way from the carboxylic acid melts at 274-276 °.

109826/1921

Example 15

. To a solution of 3.1 g of sodium in 200 ml of absolute ethanol, 21 g of m- (1-cyclohexenyl) phenol are added with stirring. As soon as this substance has dissolved, 25.8 g of ethyl ct-bromoisobutyrate are added dropwise and the mixture is then heated to 50 for 20 hours. It is evaporated on a rotary evaporator in vacuo, the residue is taken up in 300 ml of methylene chloride and the sodium bromide which has separated out is filtered off. The methylene chloride solution is 2 times with 100 ml of ice-cold 2-n. Shaken out sodium hydroxide solution, then washed neutral with water, dried over sodium sulfate and evaporated in vacuo. The residue is in
Claisen's flask is distilled in a high vacuum and the ethyl α- [m- (1-cyclohexenyl) phenoxy] isobutyrate of the formula is obtained

0-COOO ₀ H ₁ -

as a thick oil with a b.p. 140-143 ° (0.02 mm Hg).

The m- (l-cyclohexenyl) phenol used as starting material in this example can be prepared as follows:

To a vigorously stirred suspension of 6.7 g with

109826/1921

Chloroform and washed with iodine-activated Mg turnings in 250 ml of absolute ether are added in portions to a solution of 45, 5 g m-bromo-anisole in I50 ml of absolute ether, so that the Grignard reaction mildly can be maintained. The reaction is allowed to continue for an hour, the mixture is cooled to 15 and 25 g of cyclohexanone are added dropwise. After the reaction mixture has been stirred for a further 10 hours, ice and saturated ammonium chloride solution are added. Extract with ether, wash the essential I

Layers with water, dry them over sodium sulfate and evaporate in vacuo. The oily residue is in a high vacuum fractionated and the m- (l-hydroxycyclohexyl) anisole is obtained with a boiling point of 110-115 ° (0.2 mm Hg).

55j 8 g of this compound are dissolved in 200 ml of glacial acetic acid dissolved, with 100 ml 2-n. Hydrochloric acid is added and the mixture is heated to 100 ° for one hour. It is cooled to 20 °, 200 ml are added Add water and extract with ether. The essential extracts are numbered three times with 2-n. Sodium hydrogen carbonate solution washed, dried over sodium sulfate and evaporated in vacuo. In fractional distillation from a Claisenkolben one receives the m- (l-Cyclohexenyl) -anisole with bp 90-95 ° (0.1 mm Hg).

51 g of m- (l-cyclohexenyl) anisole and 120 g of pyridine hydrochloride are mixed well and for 5 hours in a Heated to 180 ° in a nitrogen atmosphere. One cools on cinnamon

109826/1921

mertemperature from, mixed with water and extracted with benzene. The benzene extracts washed three times with water are dried over sodium sulfate and evaporated in vacuo. The pale brown, oily residue is the crude m- (l-cyclohexenyl) phenol represents, which can be used directly for the implementation described above.

109826/1921

Example l6

A solution of 23.6 g of α- [m- (l-Cyelohexenyl) -phenoxy] ethyl isobutyrate in 200 ml of ethanol is mixed with 150 ml of 2-n. Sodium hydroxide solution and added for 2 hours 60 heated. It is then evaporated on a rotary evaporator in vacuo, and concentrated hydrochloric acid is added to the aqueous solution until acidic reaction and extracted with ether. The ether layer is washed neutral with water over sodium sulfate dried and evaporated in vacuo. The residue is recrystallized from ether-petroleum ether and obtained the α- [m- (l-cyclohexenyl) phenoxy] isobutyric acid of the formula

as white crystals with a temperature of 95-97 °.

The sodium salt prepared in the usual way from the carboxylic acid melts at 220-225 °.

109826/1921

Example 17

To a solution of 1.8 g of sodium in 100 ml of absolute ethanol, 12.2 g of p- (1-cyclohexenyl) phenol are added with stirring added. As soon as this substance has dissolved, 15.7 g of ethyl α-bromoisovalerate are added dropwise and then heated to 50 ° for 16 hours. After evaporation in vacuo, the residue is taken in 500 ml ml of ether, filtered off from the precipitated sodium bromide, the ether phase washes twice with 20 ml each time of ice cold 2-n. Caustic soda and with water. After drying over sodium sulfate, it is evaporated in vacuo and the crude ethyl a- [p- (1-cyclohexenyl) phenoxy] isovalerate is obtained the formula

CH

GH.

0-CH — COOG ₀ H ₁ -

as a pale yellow oil.

109826/1 9 2

Example 18

A solution of 7 S «- [ρ- (l-cyclohexenyl) phenoxy] isovaleric acid ethyl ester in 100 ml of ethanol is mixed with βθ ml of 2-n. Sodium hydroxide solution is added and the mixture is heated to 60 for 2 hours. It is then evaporated on a rotary evaporator in vacuo, the aqueous solution, which was first washed out with ether, is added with concentrated hydrochloric acid until an acidic reaction occurs, and it is extracted with ether. The ether layer is washed neutral with water, dried over sodium sulfate and evaporated in vacuo. The oily residue is distilled in a high vacuum, the a- [p- (l-cyclohexenyl) phenoxy] isovaleric acid of the formula

OH

O-CH-OOOH

obtained as a viscous oil with a b.p. 1β0-170 ° (Ο, Ο 9 mm Hg) will.

The sodium salt produced in the usual way from the carboxylic acid melts over 500.

109826/1921

Example 19

To a solution of 1.8 g of sodium in 100 ml of absolute ethanol, 12.2 g of p- (l-cyelohexenyl) phenol are added with stirring added. After the substance has dissolved, 14.7 g of ethyl α-bromo-valerate are added dropwise and heated at 50 for 16 hours. After evaporation in vacuo, the residue is taken in 200 ml of ether on, filtrate from the precipitated sodium bromide, the organic phase washes with 2-n. Caustic soda and with water, dries over sodium sulfate and evaporates in vacuo. The oily residue is distilled in a high vacuum, with one the ethyl α- [ρ- (l-cyelohexenyl) phenoxy] valerate the formula

OH ₂ -CH ₂ -CH ₃

H-COOCH, -

Obtained as a viscous oil of bp 140-145 ° (0.1 mm Hg).

109826/1921

Example 20

A solution of 5 g of ethyl α- [p- (l-cyelohexenyl) phenoxy] valerate in 100 ml of ethanol is mixed with 50 ml
2-n. Sodium hydroxide solution was added and the mixture was heated to 60 for 2 hours. It is then evaporated in vacuo, water is added and the mixture is extracted with ether. The aqueous phase is with 4-n. Hydrochloric acid acidified and seared out with ether. The over Na- f

Irium sulfate dried and evaporated in a vacuum ethereal extracts provide a solid residue from which
the a- [p ~ (l-cyclohexenyl) phenoxy] valeric acid of the formula by recrystallization from ether-petroleum ether

GH ₂ -CH ₂ -CH ₃
CH-COOH

is obtained as white crystals from P. 65-67 °.

The sodium salt prepared in the usual way from the carboxylic acid melts at 290-295 °.

109826/1921

Example 21

To a solution of 1.8 g of sodium in 100 ml of absolute ethanol, 12.2 g of p- (1-cyclohexenyl) phenol are added with stirring. As soon as the substance has dissolved, 15.7 g of ethyl α-bromobutyrate are added dropwise and the mixture is then heated at 50 for 10 hours. It is evaporated in vacuo, the residue is taken up in 300 ml of ether, the precipitated sodium bromide is filtered off and shaken with ice-cold 2N. Caustic soda and with water. After drying over sodium sulfate and evaporation in vacuo, the residue is distilled in a high vacuum, the a- [p- (l-cyclohexenyl) phenoxy] butyric acid ethyl ester of the formula

, 2 5. O-CH — COOC "H_

as a viscous oil with a bp of 147-150 ° (0.02 mm Hg).

109826/1921

Example 22

A solution of 1β g of α- [ρ- (l-cyclohexenyl) phenoxy] ethyl butyrate in 150 ml of ethanol is mixed with 130 ml of 2-n. Sodium hydroxide solution is added and the mixture is heated to 60 for 2 hours. It is then evaporated in vacuo, water is added, the mixture is extracted with ether and the aqueous layer is acidified with 2-n. Hydrochloric acid. The precipitated crystals are taken up in - * ether, washed with water and dried over sodium sulfate. After evaporation in vacuo, the solid residue is recrystallized from ether-petroleum ether, the α- [p- (l-cyclohexenyl) phenoxy] butyric acid of the form.

GH-COOH

received as white crystals from F. IO5-IO5 ⁰ . -

The sodium salt prepared in the usual way from the carboxylic acid melts at 280-285 °. Its solubility in water is at least $ 10.

109826/1921

Example 23

20 ml of ethylene glycol are added to 4.8 g of α- [p- (1-cyclohexenyl) phenoxy] butyric acid nitrile and 4.8 g of powdered sodium hydroxide, and the reaction mixture is heated to 120 for 12 hours. After cooling, 500 ml of water are added and the mixture is extracted twice with 500 ml of ether each time. The aqueous phase acidified with concentrated hydrochloric acid is extracted 3 times with 500 ml of chloroform each time. The organic phases are washed twice with 500 ml of water each time, dried over sodium sulfate and evaporated to dryness in a vacuum. A- [p- (1-cyclohexenyl) phenoxy] butyric acid from P. 100-103 , which is identical to the compounds obtained in Example 22, is obtained by crystallization from ether.

The α- [p ~ (1-cyclohexenyl) phenoxy] butyric acid nitrile used as the starting material can be obtained as follows:

1.46 g of sodium are dissolved in 70 ml of absolute ethanol and then 10 g of p- (l-cyclohexenyl) phenol. To this The mixture is slowly added dropwise with stirring at room temperature, 8.5 g of a-bromo-butyric acid nitrile. Then during 3 Stirred for hours at room temperature and overnight at 50 °. It is now evaporated to dryness in vacuo, 300 ml of ether are added to the residue and the sodium bromide is filtered off away. The Piürat is 2 times with 50 ml 2-n. Caustic soda at 0

109826/1921

extracted and dried over sodium sulfate. In the evaporation residue the organic phase which has evaporated to dryness is obtained the crude α- [p- (l-cyclohexenyl) phenoxy] butyric acid as oil, which is used directly for the hydrolysis described without further purification.

109826/1921

Example 24

5 * 2 g of crude α- [ρ- (1-cyclohexenyl) phenoxy] are heated -α-Ethyl-malonic acid in 100 ml of pyridine to boiling until no longer forms carbonic acid. Most of the pyridine is then removed in vacuo, and 200 ml are added to the residue Water, acidifies with concentrated hydrochloric acid and extracted 3 times with 200 ml of methylene chloride each time. The organic Phases are washed neutral twice with 200 ml of water each time, dried over sodium sulfate and evaporated to dryness in vacuo. Ct- [p- (1-cyclohexenyl) phenoxy] butyric acid is obtained by crystallization from ether from F. 100-103, which is identical to the compound obtained in Examples 22 and 23 is.

The α- [p- (l-cyclohexenyl) phenoxy] -α-ethyl-malonic acid used as starting material can be obtained as follows:

1.46 g of sodium are dissolved in 70 ml of absolute ethanol and then 10 g of p- (1-cyclohexenyl) phenol. 11.6 ml of a-bromo-a-ethyl-malonic acid diethyl ester are slowly added dropwise to this mixture while stirring at room temperature and stir for 16 hours at 60 °. Then it is evaporated to dryness, mixed with 300 ml of ether and the sodium bromide formed filtered off. The filtrate is extracted at 0 ° twice with 50 ml of 2-n each time. Sodium hydroxide solution, dry over sodium sulfate and evaporate

109826/1921

- oil -

dry up.

The residue is dissolved in 200 ml of ethanol and 100 ml of 2-n. Sodium hydroxide solution and leaves overnight at room temperature stand. After most of the ethanol has been removed in vacuo, the mixture is acidified with concentrated hydrochloric acid and extracted 5 times with 200 ml of ethyl acetate each time. The organic Phases are washed neutral twice with 200 ml of water each time, dried over sodium sulfate and evaporated to dryness in vacuo. The a- [p- (l-Cyclohe- * Xenyl) -phenoxyJ-α-ethyl-malonic acid can be used without further purification can be used directly for the decarboxylation described above.

ORielNAL INSPECTED Example 25

8.2 ml of n-propylamine and 7 ml of triethylamine in 100 ml of absolute tetrahydrofuran are added dropwise with stirring -5 slowly 11.7 g of α- [ρ- (l-cyclohexenyl) -phenyloxy] -isobutyric acid chloride in 20 ml of absolute tetrahydrofuran. The mixture is then stirred for a further 5 hours at room temperature. After this Removal of the solvent in vacuo is distributed at 10 between> times 200 ml of methylene chloride and 2-n. Hydrochloric acid. The organic phases are washed with sodium bicarbonate and then with water, dried over sodium sulfate and im Evaporated to dryness in vacuo. The α- [p- (l-cyclohexenyl) -phenyloxy] -isobutyric acid-n-propylamide crystallizes from pentane petroleum ether the formula

O-G-CONH-GH-CH ₂ -CH

as needles from P. 67-69 °.

The α- [ρ- (1-cyclohexenyl) phenyloxy] isobutyric acid chloride used as the starting material can be obtained as follows will:

To a slurry of 11.9 g of the sodium salt of α- [ρ- (l-cyclohexenyl) phenoxy] isobutyric acid in 200 ml absolute benzene is added at 5 ° 20 g of oxalyl chloride and

1Q9826 / 1921

leave overnight at room temperature with additional water stand. Then the common salt is filtered off and evaporated to dryness in vacuo. To completely remove the excess Oxalyl chloride, the residue is evaporated to dryness 3 times with 50 nil absolute benzene each time in vacuo. That so obtained crude, oily α- [p- (1-cyclohexenyl) phenyloxy] isobutyric acid chloride can be used directly for the reaction described above.

109626/1921

Example 26

3.0 g of 2,3-0-isopropylidene-glycerin in 20 ml of absolute pyridine and 50 ml of absolute benzene v / earth slowly with 5.5 g of et- [p- (l-cyclohexenyl) -phenoxy] - while stirring at 5 isobutyric acid chloride in 30 ml of absolute benzene. Stirring is continued for 8 hours at room temperature. For working up, 300 ml of chloroform are added and the mixture is extracted 3 times at 0 with 500 ml of water each time, then with 500 ml of 0.01 N hydrochloric acid and again with 500 ml of water. The organic phases are dried over sodium sulfate and evaporated to dryness in vacuo. The residue obtained is the α- [ρ- (ΙΟ yclohexenyl) -phenoxy] -isobutyric acid-2 _i 3-0-isopropylidene-glycerol ester of the formula

CH, CH,

GH ₃ Λ \ ^D 0 0

'-C-COO-CH ₂ -CH-OH

as OeI.

109826/1 921

- 65 -

Example 27

3ί5 δ α- [ρ- (1-cyclohexenyl) -phenoxy] -isobutyric acid-2,3-0-isopropylidene-glycerol ester in 40 ml of glacial acetic acid and 20 ml of water are briefly heated to the boil. The solution obtained is diluted with 500 ml of water, carefully neutralized at 10 with saturated soda solution and extracted 3 times with 200 ml of methylene chloride each time. The neutral washed phases Λ

are dried over sodium sulfate and evaporated to dryness in vacuo. The residue is dissolved in ethyl acetate and filtered through a column of 50 g of silica gel to decolorize. The residue from evaporation of the filtrate is obtained by chromatography pure α- [ρ- (1-cyclohexenyl) -phenoxy] -isobutyric acid-1-glycerol ester the formula

CHO 5

C-C-0-CH ₀ -CH-CH ₀ µ

² II ² i

CH ₃ "OH OH as a colorless oil. IRy _n ^ '· 3600 (s); 3 ^ 50 (s); 17 ¹ K) (s) cm" ¹ ,

109826/1921

Example 28

Ik, K ml of chloroform are added dropwise to a boiling mixture of 16.7 S of p- (1-cyclohexenyl) phenol, 56 g of sodium hydroxide and 600 ml of acetone over 15 minutes with stirring. The mixture is boiled for a further 2 hours and filtered. The filtrate is mixed with 500 ml of water, acidified with concentrated hydrochloric acid and extracted 5 times with 300 ml of ether each time. The organic phases are washed neutral, dried over sodium sulfate and evaporated in vacuo. The residue is taken up in 200 ml of cyclohexane and treated with activated charcoal. It is then filtered and evaporated in vacuo. The α- [ρ- (1-cyclohexenyl) -phenoxy] -isobutyric acid of P. II3-II5 ⁰ , which is identical to the compound obtained according to Example 4, is obtained from ether-petroleum ether.

109326/1 92 1

Example 29

55 g of ot- [p- (l-cyclohexenyl) phenoxycarbonyloxy] isobutyric acid ethyl ester are heated to 250 under nitrogen for 12 hours. Then let it cool down. The residue contains the crude α- [p- (l-cyclohexenyl) phenoxy] isobutyric acid ethyl ester, which is identical to the compound obtained in Example 5 and for identification as in Example 4 described for α- [p- (l-cyclohexenyl) phenoxy] isobutyric acid can be hydrolyzed by P. 113-115.

The ethyl α- [p- (l-cyclohexenyl) phenoxycarbonyloxy] isobutyric acid used as starting material can be obtained as follows:

To a solution of 15 g of phosgene in 150 ml of absolute Benzene is added dropwise at 0 ° at the same time, 15 g of dimethylaniline and a solution of 20 g of p- (1-cyclohexenyl) phenol in 100 ml of absolute benzene. The mixture is stirred for 5 hours at room temperature and then extracts at 0 with 0 * l-n. Hydrochloric acid. After drying the organic phase over sodium sulfate, one evaporates in a vacuum. The crude Carbo- [p-0 - Cyclohexeny3) -phenoxyJ -chloride contained in the residue is in 100 ml absolute Dissolved toluene, and with stirring to 15 g of a-hydroxy-isobutyric acid ethyl ester (Beilstein 5, 515) and 8 g of absolute pyridine in 50 ml of toluene and then added dropwise for 2 hours refluxed. The resulting solution is at 0 with 1-n. Hydrochloric acid, with caustic soda and then with water

109826 / 192T

2Ö60573

soaked, dried over sodium sulfate and in vacuo to Evaporated dry. The oily crude a- [p- (l-cyclohexenyl) phenoxycarbonyloxy] isobutyric acid ethyl ester contained in the residue can be used further directly.

10 9 8 2 6/1921

example

The following compounds can also be prepared in a manner analogous to that described in Examples 1-25 and 29:

α- [4- (1-Cyclohexenyl) -5-methyl-phenoxy] -isobutyric acid, α- [4- (1-cyclohexenyl) -5-methyl-phenoxy] -isobutyric acid ethyl ester, '. λ

α- [4- (l-Cyclohexenyl) -2-methyl-phenoxy] -isobutyric acid, α- [4- (1-Cyclohexenyl) -2-methyl-phenoxy] -isobutyric acid ethyl ester, a- [p- (2-norbornenyl) -phenoxy] -isobutyric acid, α- [ρ- (2-norbornenyl) -phenoxy] -isobutyric acid ethyl ester, α- [ρ- (l-cyclodecenyl) phenoxy] isobutyric acid and α- [p- (1-Cyclodecenyl) -phenoxy] -isobutyric acid ethyl ester.

109 826/1921 or _1G , nal .nspected

example

Tablets with a content of 0.05 g of the active Substance are made as follows;

Ingredients (for 1000 tablets):

Sodium salt of α- [p- (l-cyclooctenyl) -phenoxyj-isobutyric acid 50.0 g

Milk sugar 67.7 g

Corn starch 30.0 g

Stearic acid 1.0 g

Magnesium stearate 1.0 g

Silica gel 0.3 g

purified water q.s.

All powdery substances are individually sifted through a 0.3 mm mesh sieve and thoroughly mixed. A third of the starch and a suitable amount of water are used to make a paste for granulating the active ingredient, of the milk sugar and a third of the starch, if necessary with the addition of a further amount of water. The granulate is dried for 16 hours at 35, driven through a sieve with 1.2 mm mesh size and with the Remainder of the starch, mixed with stearic acid, magnesium stearate and silica gel and made into tablets of 0.15 g (7 »0 mm diameter), which have a breaking groove, pressed,

109826/1921

Claims (1)

Claims 1. Process for the production of a-phenoxyacetic acids in which the α-position is substituted by one or two alkyl or alkenyl radicals and the phenyl radical by a cycloaliphatic hydrocarbon radical which is only monounsaturated in the 1-position, and their esters and amides, characterized in that an ether bridge g between one Phenyl radical which is substituted by a cycloaliphatic hydrocarbon radical which is only monounsaturated in the 1-position, and an acetic acid substituted in the α-position by one or two alkyl or alkenyl radicals, or an ester or amide thereof, or in an anisole which is substituted on the benzene ring by a 1-position and only monounsaturated cycloaliphatic hydrocarbon radical and is substituted on the methyl group by one or two alkyl or alkenyl radicals and by a radical X which can be converted into a free, esterified or amidated carboxyl group, X is substituted into a free, esterified or amidated carboxyl group or converted into an ent ^{Speaking compound which carries a removable radical Y 1} in the α-position to the free or modified carboxyl group, splits off the radical Y ¹ and, if desired, introduces, modifies or splits off substituents in the compounds obtained, and / or isomer mixtures obtained 109826/1921 separates into the pure isomers and / or obtained racemates into the optical antipodes and / or obtained free compounds into their salts or obtained salts into the free compounds. 2. The method according to claim 1, characterized in that there is an ether bridge between a phenyl radical, the by one in the 1-position and only monounsaturated cycloaliphatic Hydrocarbon radical is substituted, and one in the α-position by one or two alkyl or alkenyl radicals substituted acetic acid, or an ester or amide thereof, forms or in an anisole that attaches to the benzene ring a cycloaliphatic hydrocarbon radical which is only monounsaturated in the l ~ position and is substituted on the Methyl group through one or two alkyl or alkenyl radicals and through one into a free, esterified or amidated Carboxyl group convertible radical X is substituted, X converted into a free, esterified or amidated carboxyl group, and, if desired, introduces, modifies or substitutes in the compounds obtained within the scope of the end products splits off, and / or isomer mixtures obtained into the pure isomers and / or racemates obtained into the optical antipodes separates and / or converts the free compounds obtained into their salts or the salts obtained into the free compounds. 109826/1921 3 *. Method according to claim 2, characterized in that that you can cross the Aetherbrücke by moving a by a 1-position and only monounsaturated cycloaliphatic Hydrocarbon radical substituted phenol with one reactive on the alcoholic hydroxyl group esterified and in the α-position by one or two Alkyl or alkenyl radicals substituted glycolic acid, or an ester or amide thereof, forms. 4. The method according to one of claims 2 and 3. » characterized in that the reactive esterified hydroxyl group is one with a hydrohalic acid .. or an organic sulfonic acid esterified hydroxyl group is. 5. The method according to claim 4, characterized in that that a glycolic acid is used, the alcoholic hydroxyl group of which is esterified with hydrochloric or hydrobromic acid is. 6. 'The method according to any one of claims 2-5, characterized in that the phenolic component used as an alkali metal salt. j. Method according to claim 2, characterized in that " that a mixed ester of carbonic acid can be mixed with a cyclo- 109826/1921 aliphatic hydrocarbon radical substituted phenol on the one hand and one in the α-position by one or two On the other hand, alkyl or alkenyl radicals substituted glycolic acid or an ester or amide thereof with cleavage decomposed by carbon dioxide. 8. The method according to claim 2, characterized in that X is a reactive modified carboxyl group or a trihalomethyl group. 9. The method according to claim 8, characterized in that X is the cyano group. 10. The method according to claim 8, characterized that X iot the trichloromethyl group and in the presence is hydrolyzed with a strong base. 11. The method according to any one of claims 2-10, characterized in that one starts from a compound obtainable as an intermediate at any stage of the process .. and carries out the missing process steps, or forms a starting material under the reaction conditions or a reaction component optionally in the form of it Isomers, racemates. or optical antipodes and / or in the form of their salts. 12. The method according to claim 11, characterized in that that one is a phenol that is produced by one in the 1-position and only 109826/1921 Monounsaturated cycloaliphatic hydrocarbon radical is substituted with one in the α-position one or two alkyl or alkenyl radicals substituted glycolic acid or an ester or amide thereof in the presence of an ester of carbonic acid or of a semi- esters or esters of carbonic acid in which one hydroxyl group of carbonic acid is etherified with a phenol substituted as specified above and the second hydroxyl group is etherified or replaced by a halogen atom, -and ' ä with one in the α-position by one or two alkyl- or alkenyl radicals substituted glycolic acid or an ester or amide thereof. 15. The method according to claim 12, characterized in that that "the disubstituted carbonate is a diphenyl carbonate or a di-lower alkyl carbonate. 14. The method according to claim 11, characterized in that one is a phenol, which is in the 1-position. % and only monounsaturated cycloaliphatic hydrocarbon radical is substituted, in the presence of a tri- or tetrahalogenated methane derivative and a strong base with an aldehyde or ketone derived from an alkane or alkene. 15. The method according to claim 14, characterized in that that the halogenated methane derivative is chloroform. 109826/1921 16. The method according to claim 1, characterized in, that Y 'is a carboxyl group. 17. The method according to claim 16, characterized in that that one starts from a compound obtainable as an intermediate product at any stage of the process and the missing ones Performs process steps, or forms a starting material under the reaction conditions or a reaction component optionally in the form of their isomers, racemates or optical antipodes and / or in the form of their salts begins. 18. The method according to any one of claims 2-15, characterized characterized in that esterified carboxyl groups or carbamyl groups are converted into free carboxyl groups in the compounds obtained hydrolyzed. 19. The method according to any one of claims 2-15, characterized characterized in that free or esterified carboxyl groups are converted into carbamyl groups in the compounds obtained. 20. The method according to any one of claims 2-15, characterized characterized in that free carboxyl groups are converted into esterified carboxyl groups in the compounds obtained. 1 0 9 S ? B / 1 9 2 1 ij | i | iiy: ii ::: -!:; | i »:. > !!>! Ί ||; |! Πιι! .. ιιμ; »■■!: ■ s, ■■ ,. 21. The method according to any one of claims 1, ΐβ and 17, characterized in that the reactions described in claims 18-20 are carried out. 22. The method according to any one of claims 2-15 and 18-20, characterized in that compounds are prepared in which the phenoxy radical in the meta or para position is an optionally lower alkylated 1-cycloalkenyl radical; carries and can be further substituted by lower alkyl or alkoxy groups, halogen atoms and / or Oüfluormethylgruppen, and the α-position is substituted by one or two lower alkyl radicals, as well as their esters with lower, optionally by a lower alkylamino, Nleder-alkylenamino- or optionally C-lower alkylated pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino, N'-lower alkylpierazino or N '- (hydroxy-nie'deralkyl) -piperazino group substituted alkanols, or with phenyl lower alkanols, Λ and their amides, in which the amino group is unsubstituted or a mono- or di-lower alkylamino group, a hydroxy-lower alkylamino group, a mono- or di-lower alkylamino-lower alkylamino group or an optionally C-lower alkylated pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino, N'- Nioderalkylpiperazi.no- or N ¹ - (HydroxyriiederalkyL) -piperuzLno group or a PlmnyinLod-iralkylamino group. HVi ^ , 'η Ii': 23. The method according to any one of claims 1, 16, 17 and 21, characterized in that compounds are prepared in which the phenoxy radical in the meta or para position is optionally a lower alkylated 1-cycloalkenyl radical carries and can be further substituted by lower alkyl or alkoxy groups, halogen atoms and / or trifluoromethyl groups, and the α-position is substituted by one or two lower alkyl radicals, as well as their esters with lower ones, if appropriate by a lower alkylamino, lower alkylenamino or optionally C-lower alkylated pyrrolidino, piperidino, Morpholino-, thiomorpholine-, hperazino-, N'-lower alkyl-plperazino- or N '- (hydroxy-lower alkyl) piperazino group-substituted alkanols, or with phenyl-lower alkanols, and their amides, in which the amino group is unsubstituted or a mono- or di-lower alkylamino group, a hydroxy lower alkylamino group, a mono- or di-lower alkylamirio-lower alkylamino group or an optionally C-lower alkylated pyrrolidino, piperidino, morpholino, thiomorpholino, Piperazino, N'-lower alkylpiperazino or N '- (- hydroxy-lower alkyl) -piperazino group or a paenyl lower alkylamino group. 24. Method ni'jh f.-Lnern the claim «" - '.-P> and 18-20, thereby germinated i?:!. N - i,>i;u;:; man Vexi> i tKh: ; _ri; ..- n dor Kennel BATH ORIGINAL R-Ph-O-C-CO-R ^ are prepared in which R represents an optionally lower alkylated 1-Cycloalkenylr.est with 4 - 10 ring members, Ph is a substituted optionally substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl p-phenylene radical and R, and R ₂ signify lower alkyl radicals, etc. and R, for a lower alkoxy group, an unsubstituted one Phenyl-lower alkoxy group or the free hydroxyl group and also a free amino group, a mono- or di-lower alkylamino group or can represent an unsubstituted phenyl-lower alkylamino group. 25 * method according to one of claims 2-15 and 18-20, characterized in that one compounds of the formula Γ ' * R-Ph-OC-CO-R, R ₂ produces, wherein R denotes 1-cyclopentenyl, 1-cyclohexenyl. or denotes the 1-cycloheptenyl radical, Ph for one through 109826/19? 1 Methyl, methoxy or chlorine-substituted or unsubstituted p-phenylene radical, R and R _{p is} ethyl or methyl and R is methoxy, ethoxy or the free hydroxyl group. 2β. Process according to one of Claims 1-21, characterized in that compounds of the formula R-Ph-O-C-CO-R, ι ^{5 l} R ₂ produces, wherein R denotes the 1-cyclooctenyl radical or the 1-cyclononenyl radical, Ph represents one through methyl, methoxy
or chlorine-substituted or unsubstituted p-phenylene radical, R ₁ and B. Ethyl or methyl and R-, methoxy,
Means ethoxy or the free hydroxy group. 27. "Method according to one of claims 1-15 and l8,
characterized in that the α- [p- (l-cyclooctenyl) -phenoxyj-isobutyric acid of the formula manufactures. 109826/1921 28. The method according to any one of claims 2-15 and 18, characterized characterized in that the α- [p- (l-cyclohexenyl) -phenoxyj-isobutyric acid manufactures. 29. The method according to any one of claims 2-15, 18-20, 22, 24, 25 and 28, characterized in that the new compounds are produced in free form. 30. The method according to any one of claims 1, l6, I7, 21, ^ 23, 26 and 27, characterized in that one the new Establishes connections in free form. 31. The method according to any one of claims 2-15, 18-20, 22, 24, 25 and 28, characterized in that the new compounds are prepared in the form of their salts. 32. The method according to any one of claims 1, 16, 17, 21, 23, j 26 and 27, characterized in that the new compounds are prepared in the form of their salts. 33. The compounds prepared according to any one of claims 1-32. 34. tx-phenoxy-acetic acids, in which the α-position is replaced by one or two alkyl or alkenyl radicals and the 109826/1921 Phenyl radical by one in the 1-position and only monounsaturated cycloaliphatic hydrocarbon residue? is substituted, and their esters and amides. 35 · α-phenoxyacetic acids, in which the phenoxy radical in the meta or para position an optionally lower alkylated one 1-Cycloalkenyl radical carries and even further through lower Alkyl or alkoxy groups, halogen atoms and / or trifluoromethyl groups can be substituted, and the α-position is substituted by one or two lower alkyl radicals, and their esters with lower ones, optionally by one Lower alkylamino, lower alkylenamino or optionally C-lower alkylated pyrrolidino, piperidino, morpholino, Thiomorpholino, piperazino, N'-lower alkylpiperazino or N '- (hydroxy-lower alkyl) -piperazino group Alkanols, or with phenyl lower alkanols, and their amides in which the amino group is unsubstituted or a mono- or The-lower alkylamino group, a hydroxy-lower alkylamino group, a mono- or di-lower alkylamino-lower alkylamino group or an optionally C-lower alkylated group Pyrrolidino, piperidino, morpholino, thiomorpholino, bperazino, N'-lower alkylpiperazino or N '- (hydroxy-lower alkyl) -piperazino group or a phenyl lower alkylamino group. 109826/1921 36. Compounds of the formula fr R-Ph-O-C-CO-R I ^R 2 wherein R is an optionally lower alkylated 1-cycloalkenyl radical with 4-10 ring members, Ph one if necessary by lower alkyl radicals, lower alkoxy radicals, Kalogen atoms and / or trifluoromethyl groups substituted p-phenylene radical * and R and Rp mean lower alkyl radicals and R, for a lower alkoxy group, an unsubstituted phenyl-lower alkoxy group or the free hydroxyl group and also a free amino group, a mono- or di-lower alkylaraino group or can represent an unsubstituted phenyl-lower alkylamino group. 37. Compounds of the formula R-Ph-O-C-CO-R,, I ^{5 R} 2. where R denotes 1-cyclopentenyl, 1-cyclohexenyl or cycloheptenyl radical?, Ph denotes a p-phenylene radical substituted or unsubstituted by methyl, methoxy or chlorine, R, and Rp ethyl or methyl and R, methoxy, ethoxy or means the free hydroxyl group. 109826/1921 58. Compounds of the formula 1 I. R-Ph-OC-CO-R _x , wherein R denotes the 1-cyclooctenyl or the 1-cyclononenyl radical, P, h for one substituted by methyl, methoxy or chlorine adhe unsubstituted p-phenylene radical stands, R and R ethyl or methyl and R methoxy, ethoxy or the free Means hydroxyl group. 59 · a- [p- (1-Cyclopentenyl) phenoxy] isobutyric acid. 40. α- [p- (1-Cyclohexenyl) phenoxy] isobutyric acid. 41. 'a- [p- (1-Cycloheptenyl) phenoxy] isobutyric acid. 42. α- [p- (1-Cyclohexenyl) phenoxy] propionic acid. 45. a- [p- (1-Cyclopentenyl) -phenoxy] -isobutyric acid ethyl ester. 44. Ethyl α- [p- (1-Cyclohexenyl) phenoxy] isobutyrate. 1 0 9 8 2 ß / 1 9? 1 '5 Ι ^ νψψ I ·': · ;. T = "F? - ■ Ϊ!; Π: ^ ₈₅ ._ 206Q573 45. a- [p- (l-Cycloheptenyl) phenoxy] isobutyric acid ethyl- ' ester. 46. Ethyl α- [ρ- (1-cyclohexenyl) phenoxy] propionate. 47 · et- [p- (1-cyclododecenyl) phenoxy] isobutyric acid. 48. a- [p- (1-Cyclooctenyl) phenoxy] isobutyric acid. 49 · et- [p- (4-Methyl-1-cyclohexenyl) -phenoxy] -isobutyric acid . 50. et- [m- (1-Cyclohexenyl) phenoxy] isobutyric acid. 51. cc- [p- (1-Cyclohexenyl) phenoxy] isovaleric acid. 52. et- [p- (1-Cyclohexenyl) phenoxy valeric acid. m i 55. a- [p- (1-Cyclohexenyl) phenoxy] butyric acid. 54. et- [4- (1-Cyclohexenyl) -5-methyl-phenoxy] -isobutyric acid . 55. et- [4- (1-Cyclohexenyl) -2-methyl-phenoxy] -isobutyric acid. 1 0 9 8 7 B / 1 9 2 56. a- [p- (2-Norbornenyl) phenoxy] isobutyric acid. 57 · α- [ρ- (l-Cyelodecenyl) phenoxy] isobutyric acid. 58. α- [ρ- (1-Cyclohexenyl) phenoxy] isobutyric acid jS- 'diethylaminoethyl ester. 59 · ^a ~ [p- (1-Cyclohexenyl) phenoxy] isobutyric acid n-propylamine. 60. et- [p- (1-Cyclohexenyl) -phenoxy] -isobutyric acid-1-glycerol ester. 61. α- [ρ- (1-CycTohexenyl) -phenoxy] -isobutyric acid 2,3-0-isopropylidene-1-glycerol ester. _ 62. α- [ρ- (l-Cyclododecenyl) -phenoxy] -Isobutyric acid- ethyl ester. 63. α- [p- (l-Cyclooctenyl) phenoxy] isobutyric acid ethyl ester. 64. Ethyl α- [ρ- (4-methyl-1-cyelohexenyl) phenoxy] isobutyric acid ester. 1 0 9 'i? R / 1 9 2 1 2,60573 - 87 - 65. Ethyl α- [m- (l-Cyclohexenyl) phenoxy] isobutyrate. 66. Ethyl α ~ [ρ- (1-Cyclohexenyl) phenoxy] isovaleric acid ester. 67. Ethyl α- [ρ- (1-Cyclohexenyl) phenoxy] valerate. 68. Ethyl α- [ρ- (l-cyclohexenyl) phenoxy] butyric acid ester. 69. Eth- [4- (l-Cyelohexenyl) -3-methyl-phenoxy] -isobutyric acid ethyl ester. 70. Ethyl α- [4- (1-cyclohexenyl) -2-methyl-phenoxy] -isobutyric acid ester. 71. a- [p- (2-Norbornenyl) -phenoxy] -isobutyric acid ethyl ester. 72. Ethyl a- [p- (1-Cyclodecenyl) phenoxy] isobutyric acid ester. · · 73. The compounds described in claims 34-3β in the form of their pure racemates. 109826/1921 74. Those described in claims 34-37, 42, 46 and 73 Connections in the form of their optical antipodes. 75. The in claims 38, 51-55 * 56, 60, 61, 66-68 and 71 in the form of their optical antipodes. 76. The in claims 34-37, 39-42, 73 and 74 be-φ described salt-forming compounds in free form. 77. Those described in claims 34-37, 39-42, 73 and 74 salt-forming compounds in the form of their salts. 78. Those described in claims 34-37, 39-42, 73 and 74 salt-forming compounds in the form of their therapeutically useful salts. ™ 79. Those described in claims 34-37, 39-42, 73 and 74 Compounds having a free carboxyl group in the form of their alkali metal salts. 80. The salt-forming compounds described in claims 38, 47-58 and 75 in free form. 81. Those described in claims 38, 47-58 and 75 Salt-forming compounds in the form of their salts. 109826/192 1 κ "■ ■ ■■ ■ · ■■■■■" ■ · '82. Those described in claims 38, 47-58 and 75 salt-forming compounds in the form of their therapeutically useful salts. 83. Those described in claims 38, 47-57 and 75 Compounds having a free carboxyl group in the form of their alkali metal salts. 84. The compounds described in the examples. 85 · Pharmaceutical preparations containing compounds that in any one of claims 34-37, 39-46, 73, 74, 76, 78 and 79, together with a pharmaceutical carrier material. 86. Pharmaceutical preparations containing compounds of the type shown in one of claims 38, 47-72, 75-80, 82 and 83, together with a pharmaceutical carrier material. 109826/1 9 21